Purpose

This study will evaluate the safety, pharmacokinetic (PK), pharmacodynamic (PD) activity, and preliminary anti-tumor activity of GDC-9545 as a single agent and in combination with palbociclib and/or luteinizing hormone−releasing hormone (LHRH) agonist in patients with advanced or metastatic estrogen receptor (ER)-positive (human epidermal growth factor receptor 2 [HER2]-negative) breast cancer.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
Female
Accepts Healthy Volunteers
No

Inclusion Criteria

for Dose Escalation:

- Histologically or cytologically proven diagnosis of adenocarcinoma of the breast with evidence of either locally recurrent disease not amenable to resection or radiation therapy with curative intent or with metastatic disease

- ER-positive tumor

- HER2-negative breast cancer as per local laboratory testing

- Measurable disease, or evaluable bone disease; that is, bone lesions that are lytic or mixed (lytic + sclerotic) in the absence of measurable lesion

- Required paired pre- and on-treatment tumor biopsies for participants with metastases that are safely accessible as determined by the investigator

- Advanced or metastatic ER-positive/HER2-negative breast cancer that has recurred or progressed while being treated with adjuvant endocrine therapy for a duration of at least 24 months and/or endocrine therapy in the incurable, locally advanced, or metastatic setting and derived a clinical benefit from therapy (i.e., tumor response or stable disease for at least 6 months)

- No more than 2 prior lines of treatment for advanced or metastatic breast cancer

- ≥ 2 weeks must have elapsed from the use of any other endocrine, targeted therapy or chemotherapy

- Single-Agent Cohorts (only applies to Dose Escalation): Advanced or metastatic disease that is either refractory to or intolerant of existing standard therapy or for which no effective standard therapy that confers clinical benefit is available

- Cohort B0: No prior treatment with Cyclin-Dependent Kinase (CDK) 4/6 inhibitor

- For participants undergoing 18F-fluoroestradiol-positron emission tomography (FES-PET) imaging additional restrictions on prior therapy include: ≥2 months must have elapsed from the use of tamoxifen; ≥6 months must have elapsed from the use of fulvestrant

- Postmenopausal status

- Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1

- Resolution of all acute toxic effects of prior therapy or surgical procedures to baseline or Grade ≤1 (except alopecia or other toxicities not considered to be a safety risk for the patient)

- Life expectancy of ≥12 weeks

- Adequate organ function

Inclusion Criteria for Dose Expansion:

Same as above, except:

- In South Korea: Must have received exactly 2 prior lines of treatment for advanced or metastatic breast cancer

- In the rest of the world: No more than one prior line of treatment for advanced or metastatic breast cancer

And plus:

- Cohort B1−2: No prior treatment with CDK4/6 inhibitor

- Cohorts A1, A3, and B1 only: Postmenopausal status

- Cohorts A2, A4, and B2 only: Participants not defined as post-menopausal

- No prior treatment with an oral selective estrogen receptor degrader (SERD)

- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use non-hormonal contraceptive methods with a failure rate of < 1% per year during the treatment period and for 40 days after the last dose of GDC-9545, and agreement to refrain from donating eggs

Exclusion Criteria

for Dose Escalation:

- Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms

- Current treatment with any systemic anti-cancer therapies for advanced disease

- Concurrent treatment with warfarin or phenytoin

- Diagnosis of any secondary malignancy within 3 years prior to enrollment, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer

- Active inflammatory bowel disease, chronic diarrhea, short bowel syndrome, or major upper GI surgery including gastric resection

- Known Human Immunodeficiency Virus (HIV) infection

- Known clinically significant history of liver disease consistent with Child-Pugh Class B or C, including active viral or other hepatitis (e.g., hepatitis B or hepatitis C virus), current alcohol abuse, or cirrhosis

- Major surgery within 4 weeks prior to enrollment

- Radiation therapy within 2 weeks prior to enrollment

Exclusion Criteria for Dose Expansion:

Same as above, plus:

- Pregnant, lactating, or breastfeeding

- Additional exclusion criteria for participants in Cohort B: History of venous thromboembolic event requiring therapeutic anticoagulation

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Dose Escalation: GDC-9545
During dose escalation, participants will be assigned sequentially to escalating doses of GDC-9545, up to the maximum tolerated dose (MTD) or maximum administered dose (MAD).
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
Experimental
Dose Escalation: Cohort B0: GDC-9545 + Palbociclib
GDC-9545 will be administered at a dose lower than the MTD or MAD determined in single-agent dose escalation along with the label-recommended dose of Palbociclib.
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
  • Drug: Palbociclib
    Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
Experimental
Dose Expansion: Cohort A1: GDC-9545 Dose 1
GDC-9545 will be administered as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 1).
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
Experimental
Dose Expansion: Cohort A2: GDC-9545 Dose 1 + LHRH
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD (Dose 1) along with an approved LHRH agonist.
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
  • Drug: LHRH agonist
    LHRH agonist will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. Physician will choose LHRH agonist approved for use in breast cancer.
Experimental
Dose Expansion: Cohort A3: GDC-9545 Dose 2
GDC-9545 will be administered as a single-agent at a dose that is less than or equal to the MTD/MAD (Dose 2).
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
Experimental
Dose Expansion: Cohort A4; GDC-9545 Dose 2 + LHRH
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD (Dose 2) along with an LHRH agonist.
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
  • Drug: LHRH agonist
    LHRH agonist will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. Physician will choose LHRH agonist approved for use in breast cancer.
Experimental
Dose Expansion: Cohort B1: GDC-9545 + Palbociclib
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD along with Palbociclib.
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
  • Drug: Palbociclib
    Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
Experimental
Dose Expansion: Cohort B2: GDC-9545 + Palbociclib + LHRH
GDC-9545 will be administered at a dose that is less than or equal to the MTD/MAD along with Palbociclib and an approved LHRH agonist.
  • Drug: GDC-9545
    GDC-9545 will be administered orally, once daily, on Days 1-28 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
  • Drug: Palbociclib
    Palbociclib will be administered orally, once daily, at the label-recommended dose of 125 mg on Days 1-21 of each 28-day cycle, until disease progression, unacceptable toxicity, withdrawal of consent, or study termination (approximately 21 months).
  • Drug: LHRH agonist
    LHRH agonist will be administered by injection once every 4 weeks on Day 1 of each 28-day cycle, according to the label. Physician will choose LHRH agonist approved for use in breast cancer.

Recruiting Locations

Vanderbilt University Medical Center; Vanderbilt University
Nashville, Tennessee 37232

More Details

NCT ID
NCT03332797
Status
Recruiting
Sponsor
Genentech, Inc.

Study Contact

Reference Study ID Number: GO39932 www.roche.com/about_roche/roche_worldwide.htm
888-662-6728 (U.S. Only)
global-roche-genentech-trials@gene.com

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.